Cancer is a leading cause of death in the United States. Despite the significant progress in the development of cancer detection, prevention, surgery, chemotherapy and radiation therapy, no common cure has been fully established for patients with these malignant diseases. Traditional chemotherapy relies on the premise that rapidly proliferating tumor cells are more likely to be killed by cytotoxic agents than normal cells. However, due to the little or no specificity of these cytotoxic agents, severe systemic toxicity and dose-limiting side effects may occur.
Tumor-targeting drug conjugates are designed with a tumor recognition moiety attached directly, or through a linker, to a cytotoxic agent. Synthesizing a tumor-targeting drug conjugate that is stable during blood circulation but readily cleaved to release the cytotoxic agent efficiently upon internalization into the tumor cells is, however, not always feasible. In addition, binding a cytotoxic agent to a recognition moiety can have the effect of dramatically reducing the efficacy of the cytotoxic agent, or disabling the action of the cytoxic agent completely.
Tumor-targeting prodrug delivery strategies are based on active or passive targeting. Active targeting relies on the difference between tumor-associated cell surface biomarker expression, such as antigen or receptor, and cell surface biomarker expression in normal tissue. In the past, numerous research efforts have focused on conjugating anticancer drugs with antibodies through a linker to construct a tumor-targeting drug conjugate for drug delivery. For example, monoclonal antibodies were intensively investigated in active targeting approaches because of their high binding affinity for the responding antigens.
Another more challenging strategy, classified as passive targeting, employs macromolecules, including polymers or nanoparticles, as inactive carriers or vehicles. These macromolecules are not directly interacting with tumor cells, but strongly influence the accumulation, transportation and biodistribution of their drug conjugates in tumor tissue due to the enhanced permeability and retention effect.
Dendrimer chemistry was first discovered in the 1970's. In the 1980's, the first family of dendrimers with controlled molecular weight building, controlled branching and versatility in design and modification of the reactive terminal end groups was realized.
Compared with the small molecular drug conjugates which only have a limited number of targeting moieties in each conjugate, a dendrimer employed as a macromolecular carrier can largely increase the loading capacity of the targeting moiety to achieve a high targeting concentration and efficiency at tumor sites.
It is a common issue in the polymeric medicinal chemistry field that the polymer-derived macromolecules are not a single component. Due to the steric hindrance effect of dendrimers and limitations in the purification thereof, functionalization of the surface of dendrimers usually generates multi-component derivatives which only have slight chemical differences, which result in separation difficulties. In addition, the quality of each batch depends on many factors including reaction time, temperature and reaction solvents. It is thus no guarantee that a multi-functionalized dendrimer can exhibit the same functionalities consistently. This leads to practically irreproducible results from batch to batch.
Thus, there is a need for improving, inter alia, the specificity of cytotoxic agent delivery and of tumor recognition. To achieve the above, there is a need for an improved tumor recognition moiety as well as an appropriate cleavable linker that binds the tumor recognition moiety to the cytotoxic agent.